Substituted an unsubstituted benzooxathiazoles and compounds derived therefrom

ABSTRACT

The invention relates to substituted and unsubstituted 3H-benzo[1,2,3]oxathiazole 2,2-dioxides, 1,3-dihydrobenzo[1,2,5]thiadiazole 2,2-dioxides and 1,3-dihydro-benzo[c]isothiazole 2,2-dioxides, to their preparation and to their use in medicaments.

This application claims priority to German Patent Application10038709.8-44, filed Aug. 9, 2000, which is hereby incorporated byreference, in its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to substituted and unsubstituted3H-benzo-[1,2,3]oxathiazole 2,2-dioxides,1,3-dihydrobenzo[1,2,5]thiadiazole 2,2-dioxides and1,3-dihydrobenzo[c]isothiazole 2,2-dioxides, to their preparation and totheir use in medicaments.

2. Description of the Related Art

Aminobenzosultam derivatives acting as lipoxygenase inhibitors are known(WO 92/05164). Also known is the use of corresponding bifunctionalderivatives as charge transporters in photoreceptors (JP 95/325942).Andersen et al. described the synthesis of toluenesulfonyl-protectedderivatives and studies of reactions of these derivatives withnucleophiles (K. Andersen et al., J. Phys. Org. Chem., 10, 175–181(1997); K. Andersen et al., J Org. Chem., 60, 2003–2007 (1995)).

SUMMARY OF THE INVENTION

It was an object of the present invention to provide novel substitutedand unsubstituted benzooxathiazoles and their preparation and use aspharmaceutically active compounds. In particular, it was an object toprovide novel substituted and unsubstituted benzooxathiazoles fortreating type 1 and type 2 diabetes, insulin resistance and pathologicalobesity.

The present invention relates to compounds of the formula I

in which

-   X is CH₂, O, N;-   Y is CH₂, O, N;-   R1, R2, R3 are each independently of one another    -   H, F, Cl, Br, I, NH₂, OH, NO₂, COOH;    -   COO(C₁–C₆)alkyl, CONH₂, CONH(C₁–C₁₆)alkyl, CONH(C₁–C₁₆)alkenyl,        CONH(C₁–C₆)alkyl-phenyl, where phenyl may be mono- to        trisubstituted by O—(C₁–C₁₀)alkyl or O—(C₁–C₁₀)alkyl-phenyl,        CONH(C₁–C₆)alkyl-benzimidazole, where the benzimidazole ring may        be mono- to trisubstituted by S-phenyl, wherein the S-phenyl may        be mono- to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN,        OCF₃, O—(C₁–C₁₀)alkyl, NH₂, NH(C₁–C₆)alkyl, COOH,        COO(C₁–C₆)alkyl, CONH₂;    -   O—(C₁–C₆)alkyl;    -   (C₁–C₆)alkyl, (C₂–C₆)alkenyl, (C₂–C₆)alkynyl, (C₁–C₆)alkyl-COOH,        (C₁–C₆)alkyl-aryl, where aryl may be phenyl, naphthyl, biphenyl,        thienyl or pyridyl and the aryl moiety may in each case be mono-        to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,        O—(C₁–C₁₀)alkyl, NH₂, NH(C₁–C₆)alkyl, COOH, COO(C₁–C₆)alkyl,        CONH₂;    -   Phenyl, biphenyl, 1- or 2-naphthyl, 2-,3- or 4-pyridyl, 2- or        3-furanyl or 2- or 3-thienyl, where the phenyl, biphenyl,        naphthyl, pyridyl, furanyl or thienyl rings may in each case be        mono- to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,        O—(C₁–C₁₀)alkyl, NH₂, NH(C₁–C₆)alkyl, COOH, COO(C₁–C₆)alkyl,        CONH₂;    -   (C₃–C₁₈)cycloalkyl, where in the alkyl radicals one or more        hydrogens may be replaced by fluorine or one hydrogen may be        replaced by OH, (C₁–C₆)alkyl-phenyl or O—(C₁–C₆)alkyl-phenyl,    -   NCO, NSO₃—(C₁–C₁₀)alkyl; or in each case two of the radicals R1        and R2 or R2 and R3 or R1 and R3 together form a fused aryl        radical, where aryl may be phenyl, naphthyl, biphenyl, thienyl        or pyridyl and the aryl moiety may in each case be mono- to        trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,        O—(C₁–C₁₀)alkyl, NH₂, NH(C₁–C₆)alkyl, COOH, COO(C₁–C₆)alkyl,        CONH₂;    -   or its physiologically acceptable salts or prodrugs.

The invention preferably relates to compounds of the formula I wherein

-   X is O, N;-   Y is O, N;-   R1 is H, F, Cl, Br, I, NH₂, OH, NO₂, COOH;    -   COO(C₁–C₆)alkyl, CONH₂, CONH(C₁–C₁₆)alkyl, CONH(C₁–C₁₆)alkenyl,        CONH(C₁–C₆)alkyl-phenyl, where phenyl may be mono- to        trisubstituted by O—(C₁–C₁₀)alkyl or O—(C₁–C₁₀)alkyl-phenyl,        CONH(C₁–C₆)alkyl-benzimidazole, where the benzimidazole ring may        be mono- to trisubstituted by S-phenyl, wherein the S-phenyl may        be mono- to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN,        OCF₃, O—(C₁–C₁₀)alkyl, NH₂, NH(C₁–C₆)alkyl, COOH,        COO(C₁–C₆)alkyl, CONH₂;    -   O—(C₁–C₆)alkyl;    -   (C₁–C₆)alkyl, (C₂–C₆)alkenyl, (C₂–C₆)alkynyl, (C₁–C₆)alkyl-COOH,        (C₁–C₆)alkyl-aryl, where aryl may be phenyl, naphthyl, biphenyl,        thienyl or pyridyl and the aryl moiety may in each case be mono-        to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,        O—(C₁–C₁₀)alkyl, NH₂, NH(C₁–C₆)alkyl, COOH, COO(C₁–C₆)alkyl,        CONH₂;    -   Phenyl, biphenyl, 1- or 2-naphthyl, 2-, 3- or 4-pyridyl, 2- or        3-furanyl or 2- or 3-thienyl, where the phenyl, biphenyl,        naphthyl, pyridyl, furanyl or thienyl rings may in each case be        mono- to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,        O—(C₁–C₁₀)alkyl, NH₂, NH(C₁–C₆)alkyl, COOH, COO(C₁–C₆)alkyl,        CONH₂; (C₃–C₁₈)cycloalkyl, where in the alkyl radicals one or        more hydrogens may be replaced by fluorine or one hydrogen may        be replaced by OH, (C₁–C₆)alkyl-phenyl or O—(C₁–C₆)alkyl-phenyl,    -   NCO, NSO₃—(C₁–C₁₀)alkyl;-   R2 is H, F, Cl, Br, I, NH₂, OH, NO₂, COOH;    -   COO(C₁–C₆)alkyl, CONH₂, CONH(C₁–C₁₆)alkyl, CONH(C₁–C₁₆)alkenyl,        CONH(C₁–C₆)alkyl-phenyl, where phenyl may be mono- to        trisubstituted by O—(C₁–C₁₀)alkyl or O—(C₁–C₁₀)alkyl-phenyl,        CONH(C₁–C₆)alkyl-benzimidazole, where the benzimidazole ring may        be mono- to trisubstituted by S-phenyl, wherein the S-phenyl may        be mono- to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN,        OCF₃, O—(C₁–C₁₀)alkyl, NH₂, NH(C₁–C₆)alkyl, COOH,        COO(C₁–C₆)alkyl, CONH₂;    -   O—(C₁–C₆)alkyl;    -   (C₁–C₆)alkyl, (C₂–C₆)alkenyl, (C₂–C₆)alkynyl, (C₁–C₆)alkyl-COOH,        (C₁–C₆)alkyl-aryl, where aryl may be phenyl, naphthyl, biphenyl,        thienyl or pyridyl and the aryl moiety may in each case be mono-        to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,        O—(C₁–C₁₀)alkyl, NH₂, NH(C₁–C₆)alkyl, COOH, COO(C₁–C₆)alkyl,        CONH₂;    -   Phenyl, biphenyl, 1- or 2-naphthyl, 2-, 3- or 4-pyridyl, 2- or        3-furanyl or 2- or 3-thienyl, where the phenyl, biphenyl,        naphthyl, pyridyl, furanyl or thienyl rings may in each case be        mono- to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,        O—(C₁–C₁₀)alkyl, NH₂, NH(C₁–C₆)alkyl, COOH, COO(C₁–C₆)alkyl,        CONH₂; (C₃–C₁₈)cycloalkyl, where in the alkyl radicals one or        more hydrogens may be replaced by fluorine or one hydrogen may        be replaced by OH, (C₁–C₆)alkyl-phenyl or O—(C₁–C₆)alkyl-phenyl,    -   NCO, NSO₃—(C₁–C₁₀)alkyl;-   R3 is H, F, Cl, Br, I, NH₂, OH, NO₂, COOH;    -   COO(C₁–C₆)alkyl, CONH₂, CONH(C₁–C₁₆)alkyl, CONH(C₁–C₁₆)alkenyl,        CONH(C₁–C₆)alkyl-phenyl, where phenyl may be mono- to        trisubstituted by O—(C₁–C₁₀)alkyl or O—(C₁–C₁₀)alkyl-phenyl,        CONH(C₁–C₆)alkyl-benzimidazole, where the benzimidazole ring may        be mono- to trisubstituted by S-phenyl, wherein the S-phenyl may        be mono- to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN,        OCF₃, O—(C₁–C₁₀)alkyl, NH₂, NH(C₁–C₆)alkyl, COOH,        COO(C₁–C₆)alkyl, CONH₂;    -   O—(C₁–C₆)alkyl;    -   (C₁–C₆)alkyl, (C₂–C₆)alkenyl, (C₂–C₆)alkynyl, (C₁–C₆)alkyl-COOH,        (C₁–C₆)alkyl-aryl, where aryl may be phenyl, naphthyl, biphenyl,        thienyl or pyridyl and the aryl moiety may in each case be mono-        to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,        O—(C₁–C₁₀)alkyl, NH₂, NH(C₁–C₆)alkyl, COOH, COO(C₁–C₆)alkyl,        CONH₂;    -   Phenyl, biphenyl, 1- or 2-naphthyl, 2-, 3- or 4-pyridyl, 2- or        3-furanyl or 2- or 3-thienyl, where the phenyl, biphenyl,        naphthyl, pyridyl, furanyl or thienyl rings may in each case be        mono- to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,        O—(C₁–C₁₀)alkyl, NH₂, NH(C₁–C₆)alkyl, COOH, COO(C₁–C₆)alkyl,        CONH₂; (C₃–C₁₈)cycloalkyl, where in the alkyl radicals one or        more hydrogens may be replaced by fluorine or one hydrogen may        be replaced by OH, (C₁–C₆)alkyl-phenyl or O—(C₁–C₆)alkyl-phenyl,        NCO, NSO₃—(C₁–C₁₀)alkyl;    -   or its physiologically acceptable salts or prodrugs.

The invention furthermore preferably relates to compounds of the formulaI wherein

-   X is O, N;-   Y is N;-   R1 is H, F, Cl, Br, I, NH₂, OH, NO₂, COOH;    -   COO(C₁–C₆)alkyl, CONH₂, CONH(C₁–C₁₆)alkyl, CONH(C₁–C₁₆)alkenyl,        CONH(C₁–C₆)alkyl-phenyl, where phenyl may be mono- to        trisubstituted by O—(C₁–C₁₀)alkyl or O—(C₁–C₁₀)alkyl-phenyl,        CONH(C₁–C₆)alkyl-benzimidazole, where the benzimidazole ring may        be mono- to trisubstituted by S-phenyl, wherein the S-phenyl may        be mono- to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN,        OCF₃, O—(C₁–C₁₀)alkyl, NH₂, NH(C₁–C₆)alkyl, COOH,        COO(C₁–C₆)alkyl, CONH₂;    -   O—(C₁–C₆)alkyl;    -   (C₁–C₆)alkyl, (C₂–C₆)alkenyl, (C₂–C₆)alkynyl, (C₁–C₆)alkyl-COOH,        (C₁–C₆)alkyl-aryl, where aryl may be phenyl, naphthyl, biphenyl,        thienyl or pyridyl and the aryl moiety may in each case be mono-        to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,        O—(C₁–C₁₀)alkyl, NH₂, NH(C₁–C₆)alkyl, COOH, COO(C₁–C₆)alkyl,        CONH₂;    -   Phenyl, biphenyl, 1- or 2-naphthyl, 2-, 3- or 4-pyridyl, 2- or        3-furanyl or 2- or 3-thienyl, where the phenyl, biphenyl,        naphthyl, pyridyl, furanyl or thienyl rings may in each case be        mono- to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,        O—(C₁–C₁₀)alkyl, NH₂, NH(C₁–C₆)alkyl, COOH, COO(C₁–C₆)alkyl,        CONH₂; (C₃–C₁₈)cycloalkyl, where in the alkyl radicals one or        more hydrogens may be replaced by fluorine or one hydrogen may        be replaced by OH, (C₁–C₆)alkyl-phenyl or O—(C₁–C₆)alkyl-phenyl,    -   NCO, NSO₃—(C₁–C₁₀)alkyl;-   R2 is H, F, Cl, Br, I, NH₂, OH, NO₂, COOH;    -   COO(C₁–C₆)alkyl, CONH₂, CONH(C₁–C₁₆)alkyl, CONH(C₁–C₁₆)alkenyl,        CONH(C₁–C₆)alkyl-phenyl, where phenyl may be mono- to        trisubstituted by O—(C₁–C₁₀)alkyl or O—(C₁–C₁₀)alkyl-phenyl,        CONH(C₁–C₆)alkyl-benzimidazole, where the benzimidazole ring may        be mono- to trisubstituted by S-phenyl, wherein the S-phenyl may        be mono- to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN,        OCF₃, O—(C₁–C₁₀)alkyl, NH₂, NH(C₁–C₆)alkyl, COOH,        COO(C₁–C₆)alkyl, CONH₂;    -   O—(C₁–C₆)alkyl;    -   (C₁–C₆)alkyl, (C₂–C₆)alkenyl, (C₂–C₆)alkynyl, (C₁–C₆)alkyl-COOH,        (C₁–C₆)alkyl-aryl, where aryl may be phenyl, naphthyl, biphenyl,        thienyl or pyridyl and the aryl moiety may in each case be mono-        to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,        O—(C₁–C₁₀)alkyl, NH₂, NH(C₁–C₆)alkyl, COOH, COO(C₁–C₆)alkyl,        CONH₂;    -   Phenyl, biphenyl, 1- or 2-naphthyl, 2-, 3- or 4-pyridyl, 2- or        3-furanyl or 2- or 3-thienyl, where the phenyl, biphenyl,        naphthyl, pyridyl, furanyl or thienyl rings may in each case be        mono- to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,        O—(C₁–C₁₀)alkyl, NH₂, NH(C₁–C₆)alkyl, COOH, COO(C₁–C₆)alkyl,        CONH₂; (C₃–C₁₈)cycloalkyl, where in the alkyl radicals one or        more hydrogens may be replaced by fluorine or one hydrogen may        be replaced by OH, (C₁–C₆)alkyl-phenyl or O—(C₁–C₆)alkyl-phenyl,    -   NCO, NSO₃—(C₁–C₁₀)alkyl;-   R3 is COO(C₁–C₆)alkyl, CONH₂, CONH(C₁–C₁₆)alkyl,    CONH(C₁–C₁₆)alkenyl, CONH(C₁–C₆)alkyl-phenyl, where phenyl may be    mono- to trisubstituted by O—(C₁–C₁₀)alkyl or    O—(C₁–C₁₀)alkyl-phenyl, CONH(C₁–C₆)alkyl-benzimidazole, where the    benzimidazole ring may be mono- to trisubstituted by S-phenyl,    wherein the S-phenyl may be mono- to trisubstituted by F, Cl, Br, I,    OH, CF₃, NO₂, CN, OCF₃, O—(C₁–C₁₀)alkyl, NH₂, NH(C₁–C₆)alkyl, COOH,    COO(C₁–C₆)alkyl, CONH₂;    -   O—(C₁–C₆)alkyl;    -   (C₁–C₆)alkyl, (C₂–C₆)alkenyl, (C₂–C₆)alkynyl, (C₁–C₆)alkyl-COOH,        (C₁–C₆)alkyl-aryl, where aryl may be phenyl, naphthyl, biphenyl,        thienyl or pyridyl and the aryl moiety may in each case be mono-        to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,        O—(C₁–C₁₀)alkyl, NH₂, NH(C₁–C₆)alkyl, COOH, COO(C₁–C₆)alkyl,        CONH₂;    -   Phenyl, biphenyl, 1- or 2-naphthyl, 2-, 3- or 4-pyridyl, 2- or        3-furanyl or 2- or 3-thienyl, where the phenyl, biphenyl,        naphthyl, pyridyl, furanyl or thienyl rings may in each case be        mono- to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,        O—(C₁–C₁₀)alkyl, NH₂, NH(C₁–C₆)alkyl, COOH, COO(C₁–C₆)alkyl,        CONH₂; (C₃–C₁₈)cycloalkyl, where in the alkyl radicals one or        more hydrogens may be replaced by fluorine or one hydrogen may        be replaced by OH, (C₁–C₆)alkyl-phenyl or O—(C₁–C₆)alkyl-phenyl,        NCO, NSO₃—(C₁–C₁₀)alkyl; or its physiologically acceptable salts        or prodrugs.

The invention furthermore preferably relates to compounds of the formulaI wherein

-   X is O;-   Y is N;-   R1 is H, F, Cl, Br, I, NH₂, OH, NO₂, COOH;    -   COO(C₁–C₆)alkyl, CONH₂, CONH(C₁–C₁₆)alkyl, CONH(C₁–C₁₆)alkenyl,        CONH(C₁–C₆)alkyl-phenyl, where phenyl may be mono- to        trisubstituted by O—(C₁–C₁₀)alkyl or O—(C₁–C₁₀)alkyl-phenyl,        CONH(C₁–C₆)alkyl-benzimidazole, where the benzimidazole ring may        be mono- to trisubstituted by S-phenyl, wherein the S-phenyl may        be mono- to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN,        OCF₃, O—(C₁–C₁₀)alkyl, NH₂, NH(C₁–C₆)alkyl, COOH,        COO(C₁–C₆)alkyl, CONH₂;    -   O—(C₁–C₆)alkyl;    -   (C₁–C₆)alkyl, (C₂–C₆)alkenyl, (C₂–C₆)alkynyl, (C₁–C₆)alkyl-COOH,        (C₁–C₆)alkyl-aryl, where aryl may be phenyl, naphthyl, biphenyl,        thienyl or pyridyl and the aryl moiety may in each case be mono-        to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,        O—(C₁–C₁₀)alkyl, NH₂, NH(C₁–C₆)alkyl, COOH, COO(C₁–C₆)alkyl,        CONH₂;    -   Phenyl, biphenyl, 1- or 2-naphthyl, 2-, 3- or 4-pyridyl, 2- or        3-furanyl or 2- or 3-thienyl, where the phenyl, biphenyl,        naphthyl, pyridyl, furanyl or thienyl rings may in each case be        mono- to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,        O—(C₁–C₁₀)alkyl, NH₂, NH(C₁–C₆)alkyl, COOH, COO(C₁–C₆)alkyl,        CONH₂; (C₃–C₁₈)cycloalkyl, where in the alkyl radicals one or        more hydrogens may be replaced by fluorine or one hydrogen may        be replaced by OH, (C₁–C₆)alkyl-phenyl or O—(C₁–C₆)alkyl-phenyl,    -   NCO, NSO₃—(C₁–C₁₀)alkyl;-   R2 is F, Cl, Br, I, NH₂, OH, NO₂, COOH;    -   COO(C₁–C₆)alkyl, CONH₂, CONH(C₁–C₁₆)alkyl, CONH(C₁–C₁₆)alkenyl,        CONH(C₁–C₆)alkyl-phenyl, where phenyl may be mono- to        trisubstituted by O—(C₁–C₁₀)alkyl or O—(C₁–C₁₀)alkyl-phenyl,        CONH(C₁–C₆)alkyl-benzimidazole, where the benzimidazole ring may        be mono- to trisubstituted by S-phenyl, wherein the S-phenyl may        be mono- to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN,        OCF₃, O—(C₁–C₁₀)alkyl, NH₂, NH(C₁–C₆)alkyl, COOH,        COO(C₁–C₆)alkyl, CONH₂;    -   O—(C₁–C₆)alkyl;    -   (C₁–C₆)alkyl, (C₂–C₆)alkenyl, (C₂–C₆)alkynyl, (C₁–C₆)alkyl-COOH,        (C₁–C₆)alkyl-aryl, where aryl may be phenyl, naphthyl, biphenyl,        thienyl or pyridyl and the aryl moiety may in each case be mono-        to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,        O—(C₁–C₁₀)alkyl, NH₂, NH(C₁–C₆)alkyl, COOH, COO(C₁–C₆)alkyl,        CONH₂; Phenyl, biphenyl, 1- or 2-naphthyl, 2-, 3- or 4-pyridyl,        2- or 3-furanyl or 2- or 3-thienyl, where the phenyl, biphenyl,        naphthyl, pyridyl, furanyl or thienyl rings may in each case be        mono- to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,        O—(C₁–C₁₀)alkyl, NH₂, NH(C₁–C₆)alkyl, COOH, COO(C₁–C₆)alkyl,        CONH₂;    -   (C₃–C₁₈)cycloalkyl, where in the alkyl radicals one or more        hydrogens may be replaced by fluorine or one hydrogen may be        replaced by OH, (C₁–C₆)alkyl-phenyl or O—(C₁–C₆)alkyl-phenyl,    -   NCO, NSO₃—(C₁–C₁₀)alkyl;-   R3 is COO(C₁–C₆)alkyl, CONH₂, CONH(C₁–C₁₆)alkyl,    CONH(C₁–C₁₆)alkenyl, CONH(C₁–C₆)alkyl-phenyl, where phenyl may be    mono- to trisubstituted by O—(C₁–C₁₀)alkyl or    O—(C₁–C₁₀)alkyl-phenyl, CONH(C₁–C₆)alkyl-benzimidazole, where the    benzimidazole ring may be mono- to trisubstituted by S-phenyl,    wherein the S-phenyl may be mono- to trisubstituted by F, Cl, Br, I,    OH, CF₃, NO₂, CN, OCF₃, O—(C₁–C₁₀)alkyl, NH₂, NH(C₁–C₆)alkyl, COOH,    COO(C₁–C₆)alkyl, CONH₂;    -   O—(C₁–C₆)alkyl;    -   (C₁–C₆)alkyl, (C₂–C₆)alkenyl, (C₂–C₆)alkynyl, (C₁–C₆)alkyl-COOH,        (C₁–C₆)alkyl-aryl, where aryl may be phenyl, naphthyl, biphenyl,        thienyl or pyridyl and the aryl moiety may in each case be mono-        to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,        O—(C₁–C₁₀)alkyl, NH₂, NH(C₁–C₆)alkyl, COOH, COO(C₁–C₆)alkyl,        CONH₂;    -   Phenyl, biphenyl, 1- or 2-naphthyl, 2-, 3- or 4-pyridyl, 2- or        3-furanyl or 2- or 3-thienyl, where the phenyl, biphenyl,        naphthyl, pyridyl, furanyl or thienyl rings may in each case be        mono- to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,        O—(C₁–C₁₀)alkyl, NH₂, NH(C₁–C₆)alkyl, COOH, COO(C₁–C₆)alkyl,        CONH₂; (C₃–C₁₈)cycloalkyl, where in the alkyl radicals one or        more hydrogens may be replaced by fluorine or one hydrogen may        be replaced by OH, (C₁–C₆)alkyl-phenyl or O—(C₁–C₆)alkyl-phenyl,    -   NCO, NSO₃—(C₁–C₁₀)alkyl;    -   or its physiologically acceptable salts or prodrugs.

The invention further relates to a method of inhibiting a PTPase,preferentially PTP1B, CD45, LAR, SHP-1, SHP-2, PTPa or HePTP, comprisingadministering to a subject in need thereof an effective amount of one ormore compounds of formula 1 as described above.

The invention further relates to a method of treating type 1 diabetes,type 2 diabetes, insuling resistance, or pathological obesity comprisingadministering to a subject in need thereof an effective amount of one ormore compounds of formula 1 as described above.

The invention still further relates to a method of preparing apharmaceutical composition comprising the steps of mixing one or morecompounds of formula 1 with one or more pharmaceutically acceptableexcipients and bringing this mixture into a form suitable foradministration.

Other compounds, features and advantages of the present invention willbecome apparent from the following detailed description. It should beunderstood, however, that the detailed description and the specificexamples, while indicating preferred embodiments of the invention, aregiven by way of illustration only, since various changes andmodifications within the spirit and scope of the invention will becomeapparent to those skilled in the art from this detailed description.

DETAILED DESCRIPTION OF A PREFERRED EMBODIMENT

In a compound of the formula I, X and Y in preferred embodiments may ineach case independently of one another be CH₂, O or N.

The invention relates to compounds of the formula I, in the form oftheir racemates, racemic mixtures and pure enantiomers, and to theirdiastereomers and mixtures thereof.

The alkyl, alkenyl and alkynyl radicals in the substituents R1, R2 andR3 can be either straight-chain or branched.

On account of their higher water solubility, pharmaceutically acceptablesalts are particularly suitable for medicinal applications compared withthe starting materials or base compounds. These salts must have apharmaceutically acceptable anion or cation. Suitable pharmaceuticallyacceptable acid addition salts of the compounds according to theinvention are salts of inorganic acids, such as hydrochloric acid,hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid,sulfonic acid and sulfuric acid, and of organic acids, such as, forexample, acetic acid, benzenesulfonic acid, benzoic acid, citric acid,ethanesulfonic acid, fumaric acid, gluconic acid, glycolic acid,isethionic acid, lactic acid, lactobionic acid, maleic acid, malic acid,methanesulfonic acid, succinic acid, p-toluenesulfonic acid, tartaricacid and trifluoroacetic acid. For medicinal purposes, the chlorine saltis particularly preferred. Suitable pharmaceutically acceptable basicsalts are ammonium salts, alkali metal salts (such as sodium salts andpotassium salts) and alkaline earth metal salts (such as magnesium saltsand calcium salts).

Salts having a pharmaceutically acceptable anion are likewise includedin the scope of the invention as useful intermediates for the productionor purification of pharmaceutically acceptable salts and/or for use innontherapeutic, for example in-vitro, applications.

Salts of chemical compounds of the formula I can be prepared usingcustomary methods familiar to the person skilled in the art. A salt canbe prepared, for example, by combining a chemical compound of theformula I with an inorganic or organic acid or base in a solvent ordiluent.

The term “physiologically functional derivative” used here relates toany physiologically acceptable derivative of a compound of the formula Iaccording to the invention, for example an ester, which onadministration to a mammal, such as, for example, man, is able (directlyor indirectly) to form a compound of the formula I or an activemetabolite thereof.

The physiologically functional derivatives also include prodrugs of thecompounds according to the invention. Such prodrugs can be metabolizedin vivo to a compound according to the invention. These prodrugs canthemselves be active or inactive.

The compounds according to the invention can also be present in variouspolymorphic forms, for example as amorphous and crystalline polymorphicforms. All polymorphic forms of the compounds according to the inventionare included in the scope of the invention and are a further aspect ofthe invention.

Hereinbelow, all references to “compound(s) according to formula (I)”refer to a compound/compounds of the formula (I) as described above, andto their salts, solvates and physiologically functional derivatives asdescribed herein.

The amount of a compound according to formula (I) which is necessary inorder to achieve the desired biological effect is dependent on a numberof factors, for example the specific compound selected, the intendeduse, the manner of administration and the clinical condition of thepatient. In general, the daily dose is in the range from 0.3 mg to 100mg (typically from 3 mg to 50 mg) per day per kilogram of bodyweight,for example 3–10 mg/kg/day. An intravenous dose can be, for example, inthe range from 0.3 mg to 1.0 mg/kg, which can be suitably administeredas an infusion of 10 ng to 100 ng per kilogram per minute. Suitableinfusion solutions for these purposes can contain, for example, from 0.1ng to 10 mg, typically from 1 ng to 10 mg per milliliter. Individualdoses can contain, for example, from 1 mg to 10 g of the activecompound. Thus, ampoules for injections can contain, for example, from 1mg to 100 mg, and orally administrable individual dose formulations,such as, for example, tablets or capsules, can contain, for example,from 1.0 to 1000 mg, typically from 10 to 600 mg. In the case ofpharmaceutically acceptable salts, the abovementioned weight detailsrelate to the weight of the dihydrothiazolium ion derived from the salt.For the prophylaxis or therapy of the abovementioned conditions, thecompounds according to formula (I) can be used themselves as thecompound, but they are preferably present in the form of apharmaceutical composition with a tolerable excipient. The excipientmust of course be tolerable, in the sense that it is compatible with theother constituents of the composition and is not harmful to thepatient's health. The excipient can be a solid or a liquid or both andis preferably formulated with the compound as an individual dose, forexample as a tablet which can contain from 0.05% to 95% by weight of theactive compound. Further pharmaceutically active substances can also bepresent, including further compounds according to formula (I). Thepharmaceutical compositions according to the invention can be preparedby one of the known pharmaceutical methods, which essentially consist inmixing the constituents with pharmacologically acceptable excipientsand/or auxiliaries.

Pharmaceutical compositions according to the invention are those whichare suitable for oral, rectal, topical, peroral (e.g. sublingual) andparenteral (e.g. subcutaneous, intramuscular, intradermal orintravenous) administration, although the most suitable manner ofadministration in each individual case is dependent on the nature andseverity of the condition to be treated and on the nature of thecompound according to formula (I) used in each case. Sugar-coatedformulations and sugar-coated delayed release formulations are alsoincluded in the scope of the invention. Acid-resistant and entericformulations are preferred. Suitable enteric coatings include celluloseacetate phthalate, polyvinyl acetate phthalate,hydroxypropylmethylcellulose phthalate and anionic polymers ofmethacrylic acid and methyl methacrylate.

Suitable pharmaceutical compounds for oral administration can be presentin separate units, such as, for example, capsules, cachets, lozenges ortablets which in each case contain a certain amount of the compoundaccording to formula (I); as powders or granules; as solution orsuspension in an aqueous or nonaqueous liquid; or as an oil-in-water orwater-in-oil emulsion. As already mentioned, these compositions can beprepared by any suitable pharmaceutical method which includes a step inwhich the active compound and the excipient (which can consist of one ormore additional constituents) are brought into contact. In general, thecompositions are prepared by uniform and homogeneous mixing of theactive compound with a liquid and/or finely divided solid excipient,after which the product is shaped, if necessary. Thus a tablet, forexample, can be prepared by pressing or shaping a powder or granules ofthe compound, if appropriate with one or more additional constituents.Pressed tablets can be prepared by tableting the compound infree-flowing form, such as, for example, in a powder or granules, ifappropriate mixed with a binder, lubricant, inert diluent and/or one (anumber of) surface-active/dispersing agent(s) in a suitable machine.Shaped tablets can be prepared by shaping the pulverulent compound,moistened with an inert liquid diluent, in a suitable machine.

Pharmaceutical compositions which are suitable for peroral (sublingual)administration include lozenges which contain a compound according toformula (I) with a flavoring, customarily sucrose and gum arabic ortragacanth, and pastilles which include the compound in an inert basesuch as gelatin and glycerol or sucrose and gum arabic.

Suitable pharmaceutical compositions for parenteral administrationpreferably include sterile aqueous preparations of a compound accordingto formula (I), which are preferably isotonic with the blood of theintended recipient. These preparations are preferably administeredintravenously, although the administration can also take placesubcutaneously, intramuscularly or intradermally as an injection. Thesepreparations can preferably be prepared by mixing the compound withwater and rendering the obtained solution sterile and isotonic with theblood. Injectable compositions according to the invention in generalcontain from 0.1 to 5% by weight of the active compound.

Suitable pharmaceutical compositions for rectal administration arepreferably present as individual dose suppositories. These can beprepared by mixing a compound according to formula (I) with one or moreconventional solid excipients, for example cocoa butter, and shaping theresulting mixture.

Suitable pharmaceutical compositions for topical application to the skinare preferably present as ointment, cream, lotion, paste, spray, aerosolor oil. Excipients which can be used are petroleum jelly, lanolin,polyethylene glycols, alcohols and combinations of two or more of thesesubstances. The active compound is in general present in a concentrationof from 0.1 to 15%, for example of from 0.5 to 2%, by weight of thecomposition.

Transdermal administration is also possible. Suitable pharmaceuticalcompositions for transdermal administration can be present as individualpatches which are suitable for long-term close contact with theepidermis of the patient. Such patches suitably contain the activecompound in an optionally buffered aqueous solution, dissolved and/ordispersed in an adhesive or dispersed in a polymer. A suitable activecompound concentration is from about 1% to 35%, preferably from about 3%to 15%. As a particular possibility, the active compound can be releasedby electrotransport or iontophoresis, as described, for example, inPharmaceutical Research, 2(6): 318 (1986).

The invention furthermore relates to a process for preparing thecompounds of the formula I, which comprises obtaining the compounds ofthe formula I in such a way that the procedure is according to thefollowing reaction scheme:

A benzylidenediamine of the formula II in which R1, R2 and R3 are asdefined in the sections above is reacted with sulfonediamine. Inparticular, it is possible to prepare a chemical compound of the formulaI in which X is N and Y is N in this manner.

It is also possible to prepare a compound of the present invention byreacting a 2-aminophenol of the formula III whose N group is protectedand whose substituents R1, R2 and R3 are as defined under formula I withsulfuryl chloride, followed by removal of the protective group. The Ngroup of the 2-aminophenol of the formula III is preferably protected byp-toluenesulfonyl.

Alternatively, a 2-aminophenol of the formula III in which the2-aminophenol is present without protective group is used as startingmaterial. This 2-aminophenol of the formula III whose N group is notprotected and whose substituents R1, R2 and R3 are each defined as inclaim 1 is treated with sulfonyldiimidazole under basic conditions. Thebase used can, for example, be triethylamine, a Hünig base or DBU(1,5-diazabicyclo[4.3.0]non-5-ene).

It is also possible to prepare a compound of the present invention by aprocess in which initially a 1-bromomethyl-2-nitrobenzene of the formulaIV

whose substituents R1, R2 and R3 are as defined under formula I withNa₂SO₃ (sodium sulfite) to give a compound of the formula V which isthen converted by reduction of the nitro group into the correspondinganiline. A compound of the formula I is finally obtained by heating thisaniline of the compound of the formula V.

The invention also relates to a pharmaceutical composition or medicamentwhich comprises at least one of the compounds of the formula I and/orits physiologically acceptable salts and/or their prodrugs and, ifappropriate, additional excipients.

The compounds of the formula I, and/or their physiologically acceptablesalts and/or their prodrugs can be used for preparing medicaments.

Such medicaments are suitable, in particular, for treating type 1 and 2diabetes, insulin resistance and pathological obesity. In addition, theyare also suitable for treating elevated blood lipid levels,hypertension, atherosclerosis, immune system dysfunctions, autoimmunediseases, allergic diseases such as asthma, osteoporosis, disturbedproliferation, such as cancer and psoriasis, diseases where theproduction of growth factors, hormones or cytokines which effect therelease of growth hormones is reduced or increased, infectious diseasesor disorders of the nervous system, such as Alzheimer's disease andschizophrenia.

The compounds of the formula I, and/or their physiologically acceptablesalts and/or their prodrugs can furthermore be used for preparing amedicament which inhibits a PTPase. Suitable PTPases are, in particular,PTP1B, CD45, LAR, SHP-1, SHP-2, PTPa or HePTP.

Finally, compounds of the formula I and/or their physiologicallyacceptable salts and/or their prodrugs can be used for preparing amedicament for the treatment of diseases, in particular, type 1 and 2diabetes, insulin resistance, pathological obesity, elevated blood lipidlevels, hypertension, atherosclerosis, immune system dysfunctions,autoimmune diseases, allergic diseases such as asthma, osteoporosis,disturbed proliferation, such as cancer and psoriasis, diseases wherethe production of growth factors, hormones or cytokines which effect therelease of growth hormones is reduced or increased, disorders of thenervous system such as Alzheimer's disease and schizophrenia andinfectious diseases.

The invention relates to the preparation of a medicament comprising atleast one compound of this invention, which comprises mixing the activecompound with a pharmaceutically acceptable excipient, and bringing thismixture into a form suitable for administration.

List of Abbreviations:

aa amino acids

DBU 1,5-diazabicyclo(4.3.0)non-5-ene

DMSO dimethyl sulfoxide

DTT dithiotreitol

EDTA ethylenediaminetetraacetic acid

EtOAc ethyl

EGTA ethylenebis(oxyethylenenitrilo)tetraacetic acid

h hour

HPLC high pressure liquid chromatography

MeOH methanol

MOI multiplicity of infection

MS mass spectroscopy

NMR nuclear magnetic resonance

PAGE polyacrylamide gel electrophoresis

RP reversed phase

RT room temperature

SDS sodium dodecylsulfate

TFA trifluoroacetic acid

The present invention, thus generally described, will be understood morereadily by reference to the examples listed below, which serve toillustrate the present invention without limiting it.

EXAMPLES

TABLE 1 formula I

Compound R1 R2 R3 X Y 1 7-H 6-H 5-H N N 2 7-H 6-H 5-CH₃ N O 3 7-H 6-H5-H O N 4 In positions 4 and 5, in each case two O N radicals R1 and R2or R2 and R3 or R1 and R3 together form a fused benzene radical; therespective remaining radical located in position 7 or 6 is H 5 7-H 6-NO₂5-H O N 6 7-H 6-NH₂ 5-H O N 7 7-H 6-H 5-COO(CH₃) O N 8 7-H 6-H 5-COOH ON 9 7-H 6-H 5-CON O N (CH₂—CH₂— phenyl-3,4-O- CH₂-phenyl) 10 7-H 6-H5-CON O N (CH₂-phenyl-4- O-(CH₂)₇—CH₃) 11 7-H 6-H 5-CON O N((CH₂)₁₅—CH₃) 12 7-H 6-H 5-COO(CH₃) N O 13 7-H 6-H 5-COOH N O 14 7-H 6-H5-CON N O (CH₂—CH₂— phenyl-3,4-O- CH₂-phenyl) 15 7-H 6-H 5-CON N O (CH₂-benzimidazolyl -2,5-S-phenyl)

Inhibitors of phosphatases are described, inter alia, in WO97/3974(cinnamic acid derivatives as inhibitors of PTP) which is herebyincorporated herein by reference. Unspecific phosphatase inhibition byvanadium oxo complexes and other vanadium complexes results in improvedinsulin resistance.

Enzymatic test systems for detecting phosphatase inhibition

In an in vitro assay, the compounds of the formula I were tested fortheir phosphatase-inhibiting action. Enzyme preparation and assay werecarried out as follows.

Obtaining the Enzyme Preparation:

A) Cell Culture:

-   -   Sf9 cells (=Spodoptera frugiperda cell type; obtainable from        Invitrogen) are cultivated in spinner flasks at 28° C. in        Grace's supplemented medium (Gibco-BRL) with 10%        heat-inactivated fetal calf serum (Gibco-BRL) according to the        protocol of Summers and Smith (A Manual for Methods for        Baculovirus Vectors and Insect Culture Procedures [Bulletin No.        15555]. Texas A & M University, Texas Agricultural Experiment        Station, College Station, Tex., 1987). Construction of        recombinant Baculovirus transfer vectors: cDNA encoding the        regulatory and catalytic domains of human PTP1B, but without the        carboxy-terminal hydrophobic region (corresponding to 1-299 aa)        was obtained via polymerase chain reaction using primers with        added donation sites and suitable cDNA matrices (obtainable, for        example, from Invitrogen) and then cloned in Baculovirus        expression vectors (Amersham Pharmacia Biotech.). The        recombinant Baculoviruses were prepared using the Bac-to-Bac        Baculovirus expression system (obtainable from Gibco-BRL). The        gene was cloned into the pFASTBAC donor plasmid (obtainable from        Life Technologies). The resulting plasmid was transformed into        competent DH10BAC Escherichia coli cells (obtainable from Life        Technologies). Following transposition and antibiotic selection,        the recombinant plasmid DNA of selected E. coli colonies was        isolated and then used for the transfection of Sf9 insect cells.        The virus particle in the supernatant medium was amplified three        times, up to a viral stock volume of 500 ml.        B) Production of Recombinant Protein:

Baculovirus infection of a 500 ml spinner culture of Sf9 cells wascarried out essentially as described by Summers and Smith (see above).At a density of 1–3×10⁶ cells/ml, Sf9 cells were pelleted bycentrifugation at 300 g for 5 min, the supernatant was removed and thecells were resuspended at a density of 1×10⁷ cell/ml in a suitablerecombinant viral stock (MOI 10). The culture was shaken carefully atroom temperature for 1.5 h and fresh medium was then added to a celldensity of 1×10⁶ cells/ml. The cells were then cultivated in suspensionat 28° C. for suitable periods following postinfection.

C) Cellular Fractionation and Total Cell Extracts of Infected Sf9 Cells:

Following postinfection, aliquots were subjected to an analysis ofprotein expression by SDS-PAGE and Western blot analysis. Cellularfractionation was carried out as described (Cromlish, W. and Kennedy, B.Biochem. Pharmacol. 52: 1777–1785, 1996). Total cell extracts wereobtained of 1 ml aliquots of the infected Sf9 cells after certainintervals postinfection. The pelleted cells (300×g, 5 min) were washedonce in phosphate-buffered saline (4° C.), resuspended in 50 μl of waterand broken up by repeated freezing/thawing. Protein concentrations weredetermined using the Bradford method, with bovine serum albumin asstandard.

Assay:

A) Dephosphorylation of a Phosphopeptide:

This assay is based on the release of phosphate from a consensussubstrate peptide which is detected in the nanomolar concentration rangeby the Malachite Green/ammonium molybdate method (Lanzetta, P. A.,Alvarez, L. J., Reinach, P. S., Candia, O. A. Anal Biochem. 100: 95–97,1979) adapted for the microtiter plate format. Thedodecatrisphosphopeptide, TRDIYETDYYRK (Biotrend, Cologne) correspondsto the amino acids 1142–1153 of the catalytic domain of the insulinreceptor and is (auto)phosphorylated on the tyrosine residues 1146,1150, and 1151. The recombinant hPTP1B was diluted with assay buffer (40mM Tris/HCl, pH 7.4, 1 mM EDTA, 20 mM DTT), corresponding to an activityof 1000–1500 nmol/min/mg of protein, and then preincubated (a 20 μlportion, 15 min, 30° C.) in the absence or presence of the testsubstance (5 μl) in the desired concentration (final concentration DMSO2% max.) in a total volume of 90 μl (assay buffer). To initiate thedephosphorylation reaction, the peptide substrate (10 μl, pre-warmed to30° C.) was added to the preincubated enzyme preparation with or withouttest substance (final concentration 0.2–200 μM), and the incubation wascontinued for 1 h. The reaction was terminated by addition of 100 μl ofMalachite Green hydrochloride (0.45%, 3 parts), ammonium molybdatetetrahydrate (4.2% in 4 N HCl, 1 part) and 0.5% of Tween 20 as stopsolution. Following 30 min of incubation at 22° C. for colordevelopment, the absorption at 650 nm was determined using a microtiterplate reader (Molecular Devices). Samples and blank values weredetermined in three replications. The PTP1B activity was calculated asnanomoles of released phosphate per min and mg of protein usingpotassium phosphate as standard. The inhibition of recombinant hPTP1B bytest substances was calculated as a percentage of the phosphatasecontrol. The IC₅₀ values show significant correlation with afour-parameter nonlinear logistic regression curve.

B) Cleavage of p-nitrophenyl Phosphate:

This assay is based on the change in absorption of the non-physiologicalsubstrate p-nitrophenyl phosphate during cleavage to nitrophenol understandard conditions (Tonks, N. K., Diltz, C. D:, Fischer, E. H. J. Biol.Chem. 263: 6731–6737, 1988; Burke T. R., Ye, B., Yan, X. J., Wang, S.M., Jia, Z. C., Chen, L., Zhang, Z. Y., Barford, D. Biochemistry 35:15989–15996, 1996). The inhibitors, at a suitable dilution, are pipettedto the reaction mixtures containing 0.5–5 mM of p-nitrophenyl phosphate.The following buffers were used (total volume 100 μl): (a) 100 mM sodiumacetate (pH 5.5), 50 mM NaCl, 0.1% (w/v) bovine serum albumin, 5 mMglutathione, 5 mM DTT, 0.4 mM EGTA and 1 mM EDTA; (b) 50 mM Hepes/KOH(pH 7.4), 100 mM NaCl, 0.1% (w/v) bovine serum albumin, 5 mMglutathione, 5 mM DTT and 1 mM EDTA. The reaction was started byaddition of enzyme and carried out in microtiter plates at 25° C. for 1h. The reaction was terminated by addition of 100 μl of 0.2 N NaOH. Theenzyme activity was determined by measuring the absorption at 405 nm,with suitable corrections for the absorption of the test substances andof p-nitrophenyl phosphate. The results were expressed in percent of thecontrol by comparing the amount of p-nitrophenol formed in the samplestreated with test substance (nmol/min/mg of protein) with the amount inthe untreated samples. Mean values and standard deviations werecalculated and the IC50 values were determined by regression analysis ofthe linear portion of the inhibition curves.

The test results show that the compounds of the formula I according tothe invention have an inhibitory effect on the phosphotyrosinephosphatase 1B (PTP1B). It is known that PTP1B plays an important rolein intracellular signal cascades. The compounds are therefore suitablefor treating in particular, type 1 and 2 diabetes, insulin resistanceand pathological obesity. Owing to the fact that they inhibit PTP1B, thecompounds are also suitable for treating hyperglycemia, hypertension,atherosclerosis, immune system dysfunctions, autoimmune diseases,allergic diseases such as asthma, osteoporosis, proliferationdisturbances, such as cancer and psoriasis, diseases with reduced orincreased production of growth factors, hormones or cytokines whicheffect the release of growth hormones, disorders of the nervous system,such as Alzheimer's disease and schizophrenia, and infectious diseases.

Preparation of Exemplary Compounds (Numeration According to Table 1):

Below, the preparation of some compounds is described in detail; theother compounds of the formula I were obtained in a similar manner:

Compound 1: 1,3-Dihydrobenzo[1,2,5]thiadiazole 2,2-dioxide

A solution of 1,2-phenylenediamine (91 mg, 0.84 mmol) and sulfamide (81mg, 0.84 mmol) in diglyme (2.5 ml) is stirred at 155° C. for 1.5 h.After cooling to RT, the reaction solution is poured into ice-water (15ml) and the product is extracted with ethyl acetate. The solvent isdistilled off under reduced pressure and the red residue is purified byflash chromatography (1:1 ethyl acetate/toluene).

Yield: 41 mg (35%).

¹H-NMR (D₆-DMSO): δ 10.8 (s, 2 H, NH), 6.88 (m, 2 H) aryl, 6.8 (m, 2 H)aryl.

MS (ESI-MS) 171.1 (M+1).

Compound 2: 6-Methyl-3H-benzo[1,2,3]oxathiazole 2,2-dioxide

N-(2-Hydroxy-4-methylphenyl)-4-methylbenzenesulfonamide

Pyridine (810 μl) and then, a little at a time, p-toluenesulfonylchloride (1.91 g, 10 mmol) are added to a solution of2-amino-5-methylphenol (1.23 g, 10 mmol) in CH₂Cl₂ (20 ml). The reactionmixture is stirred at 40° C. for 4 h. The solvent is distilled off underreduced pressure, ethyl acetate is added to the residue and the solid isfiltered off with suction.

Yield: 2.32 g (83%)

6-Methyl-3-(toluene-4-sulfonyl )-3H-benzo[1,2,3]oxathiazole 2,2-dioxide

At −78° C., a solution of sulfuryl chloride (450 μl, 5.41 mmol) inCH₂Cl₂ (10 ml) is slowly added dropwise to a solution ofN-(2-hydroxy-4-methylphenyl)-4-methylbenzenesulfonamide (1.5 g, 5.41mmol) and triethylamine (1.5 ml), and the mixture is stirred at −78° C.for one hour. After thawing to RT, the solvent is distilled off underreduced pressure and the residue is purified by RP chromatography.

Yield: 592 mg (32%).

6-Methyl-3H-benzo[1,2,3]oxathiazole 2,2-dioxide

6-Methyl-3-(toluene-4-sulfonyl)-3H-benzo[1,2,3]oxathiazole 2,2-dioxide(100 mg, 0.295 mmol) is dissolved in acetonitrile (5 ml). A solution ofsodium azide (of 20 mg, 0.29 mmol of sodium azide in 1 ml of H₂O) isadded to this solution, and the mixture is stirred at RT overnight. Themixture is then stirred at 60° C. for 1 h, the solvent is distilled offunder reduced pressure and the residue is purified by RP chromatography.

Yield: 47 mg (85%).

¹H-NMR (D₆-DMSO): δ 6.51 (d, 1 H, aryl), 6.45 (d, 1 H, aryl), 6.29 (m, 1H, aryl), 2.14 (s, 3 H, CH₃).

MS (ESI-MS, ES-) 184.9 (M−1).

Compound 3: 5-Methyl-3H-benzo[1,2,3]oxathiazole 2,2-dioxide

5-Methyl-3H-benzo[1,2,3]oxathiazole 2,2-dioxide was synthesized startingwith 2-amino-4-methylphenol, according to the sequence described underexample 2.

¹H-NMR (D₆-DMSO): δ 6.53 (d, 1 H, aryl), 6.23 (m, 1 H, aryl), 6.10 (dd,1 H, aryl), 2.13 (s, 3 H, CH₃).

MS (ESI-MS, ES-) 184.9 (M−1).

Compound 4: 1H-3-Oxa-2-thia-1-azacyclopenta[a]naphthyl 2,2-dioxide

1H-3-Oxa-2-thia-1-azacyclopenta[a]naphthyl 2,2-dioxide was synthesizedfrom 1-aminonaphthyl-2-ol, according to the sequence described underexample 2.

¹H-NMR (D₆-DMSO): δ 7.8 (dd, 1 H, aryl), 7.66 (dd, 1 H, aryl), 7.23 (m,2 H, aryl), 7.1 (d, 1 H aryl), 6.9 (d, 1 H, aryl).

MS (ESI-MS, ES-) 221 (M−1).

Compound 5: 6-Nitro-3H-benzo[1,2,3]oxathiazole 2,2-dioxide

A solution of 2-amino-5-nitrophenol (7.7 g, 50 mmol) in acetonitrile(300 ml) is treated with N-ethyldiisopropylamine (18.7 ml, 110 mmol) andN,N′-sulfuryldiimidazole (10.8 g, 55 mmol) and boiled at reflux for 18h. After cooling to RT, the solvent is distilled off under reducedpressure, the residue is taken up in 1 N HCl and the product isextracted with ethyl acetate. The product is then purified by flashchromatography (17:2:1, EtOAc/MeOH/H₂O).

Yield: 8.3 g (76.9%).

¹H-NMR (D₆-DMSO): δ 7.6 (dd, 1 H, aryl), 7.58 (s, 1 H, aryl), 6.55 (d, 1H, aryl).

MS (ESI-MS, ES-) 214.9 (M−1).

Compound 6: 6-Amino-3H-benzo[1,2,3]oxathiazole 2,2-dioxide

A solution of 6-nitro-3H-benzo[1,2,3]oxathiazole 2,2-dioxide (example 5)(8.1 g, 37 mmol) in methanol (250 ml) is hydrogenated at atmosphericpressure in the presence of Pd—C. The catalyst is then filtered off, theclear solution is treated with methanolic HCl (1 N) and the solvent isdistilled off under reduced pressure. The residue is dissolved inethanol and the product crystallizes after addition of diethyl ether.

Yield: 3.95 g (57.3%).

Compound 7: Methyl2,2-dioxo-2,3-dihydro-2,6-benzo[1,2,3]oxathiazole-5-carboxylate

3 g of methyl 3-amino-4-hydroxybenzoate (0.018 mol), 3.9 g ofsulfonyldiimidazole (0.02 mol) and 3 g of DBU (0.02 mol) are dissolvedin 50 ml of acetonitrile and the solution is degassed and then heated atboiling point for 3 h.

For work-up, the solution is diluted with 120 ml of ethyl acetate andextracted with 50 ml of 1 N HCl. The organic phase is dried overmagnesium sulfate and the solvent is distilled off under reducedpressure.

The crude product is used without purification for the next step.

Yield: 3.6 g (88%)

¹H-NMR (D6-DMSO): δ 7.55 (dd, 1 H, aromat.), 7.45 (d, 1 H, aromat.),7.23 (d, 1 H, aromat.), 3.85 (s, 3H, OMe). MS (ESI-MS) 230.1 (M+1).

Compound 8:2,2-Dioxo-2,3-dihydro-2,6-benzo[1,2,3]oxathiazole-5-carboxylic acid

3.3 g of compound 1 (21 mmol) are dissolved in a solution of 1.25 g ofNaOH in 70 ml of water. The reaction mixture is stirred at 25° C. for 4h.

The mixture is then acidified to pH 2 using 2N HCl and evaporated todryness. To remove the NaCl, the residue is taken up in 150 ml ofacetone and filtered, and the solvent is distilled off. The crudeproduct is used without purification for the next step.

Yield: 2.3 g (75%)

¹H-NMR (D6-DMSO): δ 7.54 (dd, 1 H, aromat.), 7.40 (d, 1 H, aromat.),7.27 (d, 1 H, aromat.). MS (ESI-MS) 216.1 (M+1).

Compound 9:N-[2-(3,4-Bisbenzyloxyphenyl)ethyl]-2,2-dioxo-2,3-dihydro-2,6-benzo[1,2,3]oxathiazole-5-carboxamide

A solution of 100 mg of compound 3 (0.46 mmol), 160 mg of2-(3,4-bisbenzyloxyphenyl)ethylamine hydrochloride (0.6 mmol), 115 mg ofEDC (0.6 mmol), 81 mg of HOBT and 260 mg of ethyldiisopropylamine in 2ml of DMF is stirred at 25° C. for 5 h.

The mixture is then diluted with 20 ml of ethyl acetate and extractedwith 10 ml of 2N HCl. The organic phase is dried over magnesium sulfateand the solvent is distilled off. The crude product is purified by HPLC(RP18, acetonitrile/water 0.1% TFA).

Yield: 66 mg (40%).

¹H-NMR (D6-DMSO): δ 8.49 (t, 1H, NH), 7.46–7.23 (m, 13 H, aromat.), 6.97(d, 2 H, aromat.), 6.74 (dd, 1 H, aromat.), 5.08 (s, 4H, OCH₂), 3.43(dt, 2H, NCH₂), 2.74 (2H, t, CH₂). MS (ESI-MS) 531.2 (M+1).

Compound 10:N-(4-Octyloxybenzyl)-2,2-dioxo-2,3-dihydro-2,6-benzo[1,2,3]oxathiazole-5-carboxamide4

Compound 4 is prepared as described for compound 3.

Yield: 63 mg (52%)

¹H-NMR (D6-DMSO): δ 8.95 (t, 1 H, NH), 7.52 (dd, 1 H, aromat.), 7.45 (d,1 H, aromat.), 7.3 (d, 1 H, aromat.), 7.22 (d, 2 H, aromat.), 6.86 (d, 2H, aromat.), 4.37 (d, 2H, NCH₂), 3.91 (t, 2H, OCH₂), 1.65 (m, 2H, CH₂),1.45–1.2 (m, 10H, CH₂), 0.86 (t, 3H, CH₃). MS (ESI-MS) 433.2 (M+1).

Compound 11:N-Hexadecyl-2,2-dioxo-2,3-dihydro-2,6-benzo[1,2,3]oxathiazole-5-carboxamide5

Compound 5 is prepared as described for compound 3.

Yield: 51 mg (26%)

¹H-NMR (D6-DMSO): δ 8.35 (t, 1H, NH), 7.38 (d, 1 H, aromat.), 7.34 (s, 1H, aromat.), 7.2 (d, 1 H, aromat.), 3.21 (dt, 2H, NCH₂), 1.5 (m, 2H,CH₂), 1.4 (m, 26H, CH₂), 0.85 (t, 3H, CH₃). MS (ESI-MS) 439.3 (M+1).

Compound 12: Methyl2,2-dioxo-2,3-dihydro-2,6-benzo[1,2,3]oxathiazole-6-carboxylate 6

Compound 6 is prepared as described for compound 1.

Yield: 3.35 g (82%)

¹H-NMR (D6-DMSO): δ 7.43 (dd, 1 H, aromat.), 7.19 (d, 1 H, aromat.),6.53 (d, 1 H, aromat.). MS (ESI-MS) 227.9 (M−1).

Compound 13:2,2-Dioxo-2,3-dihydro-2,6-benzo[1,2,3]oxathiazole-6-carboxylic acid 7

Compound 7 is prepared from 6 as described for compound 2.

Yield: 2.2 g (71%)

¹H-NMR (D6-DMSO): δ 7.46 (dd, 1 H, aromat.), 7.25 (d, 1 H, aromat.),6.46 (d,1 H, aromat.) 3.73 (s, 3H, Ome). MS (ESI-MS) 213.9 (M−1).

Compound 14:N-[2-(3,4-Bisbenzyloxyphenyl)ethyl]-2,2-dioxo-2,3-dihydro-2,6-benzo[1,2,3]oxathiazole-6-carboxamide8

Compound 8 is prepared from 7 as described for compound 3.

Yield: 4.1 g (25%)

¹H-NMR (D6-DMSO): δ 8.33 (t, 1H, NH), 7.55 (m, 2 H, aromat.), 7.45–7.3(m, 10 H, aromat.), 6.96 (d, 2 H, aromat.), 6.86 (d, 1 H, aromat.), 6.74(dd, 1H, aromat.), 5.08 (s, 4H, OCH₂), 3.41 (dt, 2H, NCH₂), 2.73 (2H, t,CH₂). MS (ESI-MS) 531.3 (M+1).

Compound 15:N-(5-Phenylsulfanyl-1H-benzoimidazol-2-ylmethyl)-2,2-dioxo-2,3-dihydro-2,6-benzo[1,2,3]oxathiazole-6-carboxamide9

Compound 9 is prepared from 7 as described for compound 3.

Yield: 6.9 g (34%)

¹H-NMR (D6-DMSO): δ 8.96 (t,1H, NH), 7.75 (d, 1 H, aromat.), 7.61 (d,1H, aromat.), 7.46, (m, 2H, aromat.) 7.41–7.3 (m, 6 H, aromat.), 6.55(d, 1 H, aromat.), 4.81 (d, 2H, NCH₂). MS (ESI-MS) 453.2 (M+1).

Additional advantages, features and modifications will readily occur tothose skilled in the art. Therefore, the invention in its broaderaspects is not limited to the specific details, and representativedevices, shown and described herein. Accordingly, various modificationsmay be made without departing from the spirit or scope of the generalinventive concept as defined by the appended claims and theirequivalents.

As used herein and in the following claims, articles such as “the”, “a”and “an” can connote the singular or the plural.

All documents referred to herein are specifically incorporated herein byreference in their entireties.

1. A compound of the formula I

in which X is CH₂, O or NH; Y is CH₂, O or NH; R1, R2, R3 are eachindependently of one another OH, COOH; CONH₂, CONH(C₁–C₁₆)alkyl,CONH(C₁–C₁₆)alkenyl, CONH(C₁–C₆)alkyl-phenyl, where phenyl may be mono-to trisubstituted by O—(C₁–C₁₀)alkyl or O—(C₁–C₁₀)alkyl-phenyl,CONH(C₁–C₆)alkyl-benzimidazole, where the benzimidazole ring may bemono- to trisubstituted by S-phenyl, wherein the S-phenyl may be mono-to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,O—(C₁–C₁₀)alkyl, NH₂, NH(C₁–C₆)alkyl, COOH, COO(C₁–C₆)alkyl, CONH₂;(C₂–C₆)alkenyl, (C₂–C₆)alkynyl, (C₁–C₆)alkyl-COOH, (C₁–C₆)alkyl-aryl,where aryl may be phenyl, naphthyl, biphenyl, thienyl or pyridyl and thearyl moiety may in each case be mono- to trisubstituted by F, Cl, Br, I,OH, CF₃, NO₂, CN, OCF₃, O—(C₁–C₁₀)alkyl, NH₂, NH(C₁–C₆)alkyl, COOH,COO(C₁–C₆)alkyl, CONH₂; Phenyl, biphenyl, 1- or 2-naphthyl, 2-,3- or4-pyridyl, 2- or 3-furanyl or 2- or 3-thienyl, where the phenyl,biphenyl, naphthyl, pyridyl, furanyl or thienyl rings may in each casebe mono- to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,O—(C₁–C₁₀)alkyl, NH₂, NH(C₁–C₆)alkyl, COOH, COO(C₁–C₆)alkyl, CONH₂;(C₃–C₁₈)cycloalkyl, where in the alkyl radicals one or more hydrogensmay be replaced by fluorine or one hydrogen may be replaced by OH,(C₁–C₆)alkyl-phenyl or O—(C₁–C₆)alkyl-phenyl, NCO, NSO₃—(C₁–C₁₀)alkyl;or in each case two of the radicals R1 and R2 or R2 and R3 or R1 and R3together form a fused aryl radical, where aryl may be phenyl, naphthyl,biphenyl, thienyl or pyridyl and the aryl moiety may in each case bemono- to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,O—(C₁–C₁₀)alkyl, NH₂, NH(C₁–C₆)alkyl, COOH, COO(C₁–C₆)alkyl, CONH₂; orits physiologically acceptable salts or prodrugs.
 2. A compound of theformula I as claimed in claim 1, wherein X is O or NH; Y is O or NH; R1is OH, COOH; CONH₂, CONH(C₁–C₁₆)alkyl, CONH(C₁–C₁₆)alkenyl,CONH(C₁–C₆)alkyl-phenyl, where phenyl may be mono- to trisubstituted byO—(C₁–C₁₀)alkyl or O—(C₁–C₁₀)alkyl-phenyl,CONH(C₁–C₆)alkyl-benzimidazole, where the benzimidazole ring may bemono- to trisubstituted by S-phenyl, wherein the S-phenyl may be mono-to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,O—(C₁–C₁₀)alkyl, NH₂, NH(C₁–C₆)alkyl, COOH, COO(C₁–C₆)alkyl, CONH₂;(C₂–C₆)alkenyl, (C₂–C₆)alkynyl, (C₁–C₆)alkyl-COOH, (C₁–C₆)alkyl-aryl,where aryl may be phenyl, naphthyl, biphenyl, thienyl or pyridyl and thearyl moiety may in each case be mono- to trisubstituted by F, Cl, Br, I,OH, CF₃, NO₂, CN, OCF₃, O—(C₁–C₁₀)alkyl, NH₂, NH(C₁–C₆)alkyl, COOH,COO(C₁–C₆)alkyl, CONH₂; Phenyl, biphenyl, 1- or 2-naphthyl, 2-, 3- or4-pyridyl, 2- or 3-furanyl or 2- or 3-thienyl, where the phenyl,biphenyl, naphthyl, pyridyl, furanyl or thienyl rings may in each casebe mono- to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,O—(C₁–C₁₀)alkyl, NH₂, NH(C₁–C₆)alkyl, COOH, COO(C₁–C₆)alkyl, CONH₂;(C₃–C₁₈)cycloalkyl, where in the alkyl radicals one or more hydrogensmay be replaced by fluorine or one hydrogen may be replaced by OH,(C₁–C₆)alkyl-phenyl or O—(C₁–C₆)alkyl-phenyl, NCO, NSO₃—(C₁–C₁₀)alkyl;R2 is OH, COOH; CONH₂, CONH(C₁–C₁₆)alkyl, CONH(C₁–C₁₆)alkenyl,CONH(C₁–C₆)alkyl-phenyl, where phenyl may be mono- to trisubstituted byO—(C₁–C₁₀)alkyl or O—(C₁–C₁₀)alkyl-phenyl,CONH(C₁–C₆)alkyl-benzimidazole, where the benzimidazole ring may bemono- to trisubstituted by S-phenyl, wherein the S-phenyl may be mono-to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,O—(C₁–C₁₀)alkyl, NH₂, NH(C₁–C₆)alkyl, COOH, COO(C₁–C₆)alkyl, CONH₂;(C₂–C₆)alkenyl, (C₂–C₆)alkynyl, (C₁–C₆)alkyl-COOH, (C₁–C₆)alkyl-aryl,where aryl may be phenyl, naphthyl, biphenyl, thienyl or pyridyl and thearyl moiety may in each case be mono- to trisubstituted by F, Cl, Br, I,OH, CF₃, NO₂, CN, OCF₃, O—(C₁–C₁₀)alkyl, NH₂, NH(C₁–C₆)alkyl, COOH,COO(C₁–C₆)alkyl, CONH₂; Phenyl, biphenyl, 1- or 2-naphthyl, 2-, 3- or4-pyridyl, 2- or 3-furanyl or 2- or 3-thienyl, where the phenyl,biphenyl, naphthyl, pyridyl, furanyl or thienyl rings may in each casebe mono- to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,O—(C₁–C₁₀)alkyl, NH₂, NH(C₁–C₆)alkyl, COOH, COO(C₁–C₆)alkyl, CONH₂;(C₃–C₁₈)cycloalkyl, where in the alkyl radicals one or more hydrogensmay be replaced by fluorine or one hydrogen may be replaced by OH,(C₁–C₆)alkyl-phenyl or O—(C₁–C₆)alkyl-phenyl, NCO, NSO₃—(C₁–C₁₀)alkyl;R3 is OH, COOH; CONH₂, CONH(C₁–C₁₆)alkyl, CONH(C₁–C₁₆)alkenyl,CONH(C₁–C₆)alkyl-phenyl, where phenyl may be mono- to trisubstituted byO—(C₁–C₁₀)alkyl or O—(C₁–C₁₀)alkyl-phenyl,CONH(C₁–C₆)alkyl-benzimidazole, where the benzimidazole ring may bemono- to trisubstituted by S-phenyl, wherein the S-phenyl may be mono-to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,O—(C₁–C₁₀)alkyl, NH₂, NH(C₁–C₆)alkyl, COOH, COO(C₁–C₆)alkyl, CONH₂;(C₂–C₆)alkenyl, (C₂–C₆)alkynyl, (C₁–C₆)alkyl-COOH, (C₁–C₆)alkyl-aryl,where aryl may be phenyl, naphthyl, biphenyl, thienyl or pyridyl and thearyl moiety may in each case be mono- to trisubstituted by F, Cl, Br, I,OH, CF₃, NO₂, CN, OCF₃, O—(C₁–C₁₀)alkyl, NH₂, NH(C₁–C₆)alkyl, COOH,COO(C₁–C₆)alkyl, CONH₂; Phenyl, biphenyl, 1- or 2-naphthyl, 2-, 3- or4-pyridyl, 2- or 3-furanyl or 2- or 3-thienyl, where the phenyl,biphenyl, naphthyl, pyridyl, furanyl or thienyl rings may in each casebe mono- to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,O—(C₁–C₁₀)alkyl, NH₂, NH(C₁–C₆)alkyl, COOH, COO(C₁–C₆)alkyl, CONH₂;(C₃–C₁₈)cycloalkyl, where in the alkyl radicals one or more hydrogensmay be replaced by fluorine or one hydrogen may be replaced by OH,(C₁–C₆)alkyl-phenyl or O—(C₁–C₆)alkyl-phenyl, NCO, NSO₃—(C₁–C₁₀)alkyl;or its physiologically acceptable salts or prodrugs.
 3. A compound ofthe formula I as claimed in claim 1, wherein X is O or NH; Y is NH; R1is OH, COOH; CONH₂, CONH(C₁–C₁₆)alkyl, CONH(C₁–C₁₆)alkenyl,CONH(C₁–C₆)alkyl-phenyl, where phenyl may be mono- to trisubstituted byO—(C₁–C₁₀)alkyl or O—(C₁–C₁₀)alkyl-phenyl,CONH(C₁–C₆)alkyl-benzimidazole, where the benzimidazole ring may bemono- to trisubstituted by S-phenyl, wherein the S-phenyl may be mono-to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,O—(C₁–C₁₀)alkyl, NH₂, NH(C₁–C₆)alkyl, COOH, COO(C₁–C₆)alkyl, CONH₂;(C₂–C₆)alkenyl, (C₂–C₆)alkynyl, (C₁–C₆)alkyl-COOH, (C₁–C₆)alkyl-aryl,where aryl may be phenyl, naphthyl, biphenyl, thienyl or pyridyl and thearyl moiety may in each case be mono- to trisubstituted by F, Cl, Br, I,OH, CF₃, NO₂, CN, OCF₃, O—(C₁–C₁₀)alkyl, NH₂, NH(C₁–C₆)alkyl, COOH,COO(C₁–C₆)alkyl, CONH₂; Phenyl, biphenyl, 1- or 2-naphthyl, 2-, 3- or4-pyridyl, 2- or 3-furanyl or 2- or 3-thienyl, where the phenyl,biphenyl, naphthyl, pyridyl, furanyl or thienyl rings may in each casebe mono- to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,O—(C₁–C₁₀)alkyl, NH₂, NH(C₁–C₆)alkyl, COOH, COO(C₁–C₆)alkyl, CONH₂;(C₃–C₁₈)cycloalkyl, where in the alkyl radicals one or more hydrogensmay be replaced by fluorine or one hydrogen may be replaced by OH,(C₁–C₆)alkyl-phenyl or O—(C₁–C₆)alkyl-phenyl, NCO, NSO₃—(C₁–C₁₀)alkyl;R2 is OH, COOH; CONH₂, CONH(C₁–C₁₆)alkyl, CONH(C₁–C₁₆)alkenyl,CONH(C₁–C₆)alkyl-phenyl, where phenyl may be mono- to trisubstituted byO—(C₁–C₁₀)alkyl or O—(C₁–C₁₀)alkyl-phenyl,CONH(C₁–C₆)alkyl-benzimidazole, where the benzimidazole ring may bemono- to trisubstituted by S-phenyl, wherein the S-phenyl may be mono-to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,O—(C₁–C₁₀)alkyl, NH₂, NH(C₁–C₆)alkyl, COOH, COO(C₁–C₆)alkyl, CONH₂;(C₂–C₆)alkenyl, (C₂–C₆)alkynyl, (C₁–C₆)alkyl-COOH, (C₁–C₆)alkyl-aryl,where aryl may be phenyl, naphthyl, biphenyl, thienyl or pyridyl and thearyl moiety may in each case be mono- to trisubstituted by F, Cl, Br, I,OH, CF₃, NO₂, CN, OCF₃, O—(C₁–C₁₀)alkyl, NH₂, NH(C₁–C₆)alkyl, COOH,COO(C₁–C₆)alkyl, CONH₂; Phenyl, biphenyl, 1- or 2-naphthyl, 2-, 3- or4-pyridyl, 2- or 3-furanyl or 2- or 3-thienyl, where the phenyl,biphenyl, naphthyl, pyridyl, furanyl or thienyl rings may in each casebe mono- to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,O—(C₁–C₁₀)alkyl, NH₂, NH(C₁–C₆)alkyl, COOH, COO(C₁–C₆)alkyl, CONH₂;(C₃–C₁₈)cycloalkyl, where in the alkyl radicals one or more hydrogensmay be replaced by fluorine or one hydrogen may be replaced by OH,(C₁–C₆)alkyl-phenyl or O—(C₁–C₆)alkyl-phenyl, NCO, NSO₃—(C₁–C₁₀)alkyl;R3 is COO(C₁–C₆)alkyl, CONH₂, CONH(C₁–C₁₆)alkyl, CONH(C₁–C₁₆)alkenyl,CONH(C₁–C₆)alkyl-phenyl, where phenyl may be mono- to trisubstituted byO—(C₁–C₁₀)alkyl or O—(C₁–C₁₀)alkyl-phenyl,CONH(C₁–C₆)alkyl-benzimidazole, where the benzimidazole ring may bemono- to trisubstituted by S-phenyl, wherein the S-phenyl may be mono-to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,O—(C₁–C₁₀)alkyl, NH₂, NH(C₁–C₆)alkyl, COOH, COO(C₁–C₆)alkyl, CONH₂;O—(C₁–C₆)alkyl; (C₁–C₆)alkyl, (C₂–C₆)alkenyl, (C₂–C₆)alkynyl,(C₁–C₆)alkyl-COOH, (C₁–C₆)alkyl-aryl, where aryl may be phenyl,naphthyl, biphenyl, thienyl or pyridyl and the aryl moiety may in eachcase be mono- to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,O—(C₁–C₁₀)alkyl, NH₂, NH(C₁–C₆)alkyl, COOH, COO(C₁–C₆)alkyl, CONH₂;Phenyl, biphenyl, 1- or 2-naphthyl, 2-, 3- or 4-pyridyl, 2- or 3-furanylor 2- or 3-thienyl, where the phenyl, biphenyl, naphthyl, pyridyl,furanyl or thienyl rings may in each case be mono- to trisubstituted byF, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃, O—(C₁–C₁₀)alkyl, NH₂,NH(C₁–C₆)alkyl, COOH, COO(C₁–C₆)alkyl, CONH₂; (C₃–C₁₈)cycloalkyl, wherein the alkyl radicals one or more hydrogens may be replaced by fluorineor one hydrogen may be replaced by OH, (C₁–C₆)alkyl-phenyl orO—(C₁–C₆)alkyl-phenyl, NCO, NSO₃—(C₁–C₁₀)alkyl; or its physiologicallyacceptable salts or prodrugs.
 4. A compound of the formula I as claimedin claim 1, wherein X is O; Y is NH; R1 is OH, COOH; CONH₂,CONH(C₁–C₁₆)alkyl, CONH(C₁–C₁₆)alkenyl, CONH(C₁–C₆)alkyl-phenyl, wherephenyl may be mono- to trisubstituted by O—(C₁–C₁₀)alkyl orO—(C₁–C₁₀)alkyl-phenyl, CONH(C₁–C₆)alkyl-benzimidazole, where thebenzimidazole ring may be mono- to trisubstituted by S-phenyl, whereinthe S-phenyl may be mono- to trisubstituted by F, Cl, Br, I, OH, CF₃,NO₂, CN, OCF₃, O—(C₁–C₁₀)alkyl, NH₂, NH(C₁–C₆)alkyl, COOH,COO(C₁–C₆)alkyl, CONH₂; (C₂–C₆)alkenyl, (C₂–C₆)alkynyl,(C₁–C₆)alkyl-COOH, (C₁–C₆)alkyl-aryl, where aryl may be phenyl,naphthyl, biphenyl, thienyl or pyridyl and the aryl moiety may in eachcase be mono- to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,O—(C₁–C₁₀)alkyl, NH₂, NH(C₁–C₆)alkyl, COOH, COO(C₁–C₆)alkyl, CONH₂;Phenyl, biphenyl, 1- or 2-naphthyl, 2-, 3- or 4-pyridyl, 2- or 3-furanylor 2- or 3-thienyl, where the phenyl, biphenyl, naphthyl, pyridyl,furanyl or thienyl rings may in each case be mono- to trisubstituted byF, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃, O—(C₁–C₁₀)alkyl, NH₂,NH(C₁–C₆)alkyl, COOH, COO(C₁–C₆)alkyl, CONH₂; (C₃–C₁₈)cycloalkyl, wherein the alkyl radicals one or more hydrogens may be replaced by fluorineor one hydrogen may be replaced by OH, (C₁–C₆)alkyl-phenyl orO—(C₁–C₆)alkyl-phenyl, NCO, NSO₃—(C₁–C₁₀)alkyl; R2 is OH, COOH;COO(C₁–C₆)alkyl, CONH₂, CONH(C₁–C₁₆)alkyl, CONH(C₁–C₁₆)alkenyl,CONH(C₁–C₆)alkyl-phenyl, where phenyl may be mono- to trisubstituted byO—(C₁–C₁₀)alkyl or O—(C₁–C₁₀)alkyl-phenyl,CONH(C₁–C₆)alkyl-benzimidazole, where the benzimidazole ring may bemono- to trisubstituted by S-phenyl, wherein the S-phenyl may be mono-to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,O—(C₁–C₁₀)alkyl, NH₂, NH(C₁–C₆)alkyl, COOH, COO(C₁–C₆)alkyl, CONH₂;(C₂–C₆)alkenyl, (C₂–C₆)alkynyl, (C₁–C₆)alkyl-COOH, (C₁–C₆)alkyl-aryl,where aryl may be phenyl, naphthyl, biphenyl, thienyl or pyridyl and thearyl moiety may in each case be mono- to trisubstituted by F, Cl, Br, I,OH, CF₃, NO₂, CN, OCF₃, O—(C₁–C₁₀)alkyl, NH₂, NH(C₁–C₆)alkyl, COOH,COO(C₁–C₆)alkyl, CONH₂; Phenyl, biphenyl, 1- or 2-naphthyl, 2-, 3- or4-pyridyl, 2- or 3-furanyl or 2- or 3-thienyl, where the phenyl,biphenyl, naphthyl, pyridyl, furanyl or thienyl rings may in each casebe mono- to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,O—(C₁–C₁₀)alkyl, NH₂, NH(C₁–C₆)alkyl, COOH, COO(C₁–C₆)alkyl, CONH₂;(C₃–C₁₈)cycloalkyl, where in the alkyl radicals one or more hydrogensmay be replaced by fluorine or one hydrogen may be replaced by OH,(C₁–C₆)alkyl-phenyl or O—(C₁–C₆)alkyl-phenyl, NCO, NSO₃—(C₁–C₁₀)alkyl;R3 is COO(C₁–C₆)alkyl; CONH₂, CONH(C₁–C₁₆)alkyl, CONH(C₁–C₁₆)alkenyl,CONH(C₁–C₆)alkyl-phenyl, where phenyl may be mono- to trisubstituted byO—(C₁–C₁₀)alkyl or O—(C₁–C₁₀)alkyl-phenyl,CONH(C₁–C₆)alkyl-benzimidazole, where the benzimidazole ring may bemono- to trisubstituted by S-phenyl, wherein the S-phenyl may be mono-to trisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,O—(C₁–C₁₀)alkyl, NH₂, NH(C₁–C₆)alkyl, COOH, COO(C₁–C₆)alkyl, CONH₂;O—(C₁–C₆)alkyl; (C₂–C₆)alkenyl, (C₂–C₆)alkynyl, (C₁–C₆)alkyl-COOH,(C₁–C₆)alkyl-aryl, where aryl may be phenyl, naphthyl, biphenyl, thienylor pyridyl and the aryl moiety may in each case be mono- totrisubstituted by F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃, O—(C₁–C₁₀)alkyl,NH₂, NH(C₁–C₆)alkyl, COOH, COO(C₁–C₆)alkyl, CONH₂; Phenyl, biphenyl, 1-or 2-naphthyl, 2-,3- or 4-pyridyl, 2- or 3-furanyl or 2- or 3-thienyl,where the phenyl, biphenyl, naphthyl, pyridyl, furanyl or thienyl ringsmay in each case be mono- to trisubstituted by F, Cl, Br, I, OH, CF₃,NO₂, CN, OCF₃, O—(C₁–C₁₀)alkyl, NH₂, NH(C₁–C₆)alkyl, COOH,COO(C₁–C₆)alkyl, CONH₂; (C₃–C₁₈)cycloalkyl, where in the alkyl radicalsone or more hydrogens may be replaced by fluorine or one hydrogen may bereplaced by OH, (C₁–C₆)alkyl-phenyl or O—(C₁–C₆)alkyl-phenyl, NCO,NSO₃—(C₁–C₁₀)alkyl; or its physiologically acceptable salts or prodrugs.5. A pharmaceutical composition comprising an effective amount of atleast one compound as claimed in claim 1 and a pharmaceuticallyacceptable excipient.
 6. A method of preparing a pharmaceuticalcomposition comprising the steps of mixing one or more compounds ofclaim 1 with one or more pharmaceutically acceptable excipients andbringing this mixture into a form suitable for administration.